Recently, a large number of proteins, polypeptides, synthetic compounds, and compounds extracted from natural resources having physiological activity have been found out and the application thereof to pharmaceuticals has been extensively studied. However, these physiologically active substances have short half-lives in blood when they are administrated to a living body and hence it is difficult to obtain a sufficient pharmacological effect. This is because the physiologically active substances administrated to a living body are usually cleared from the living body because of the filtration through glomeruli in the kidney and the uptake by macrophages in the liver, spleen, and the like. Therefore, it is attempted to improve the behavior in a living body by encapsulating these physiologically active substances in liposomes or polymer micelles or increasing their molecular weight through chemical modification with a polyalkylene glycol derivative which is an amphiphatic polymer. A polyalkylene glycol exhibits a low interaction with the other bio-components owing to its steric repulsion effect and as a result, proteins and polypeptides such as enzymes modified with a polyalkylene glycol derivative exhibit an effect of avoiding the filtration through glomeruli in the kidney and bio-reactions such as immunoreaction, so that they achieve half-lives in blood longer than those of unmodified substances. It is known that this effect is larger when the molecular weight of the polyalkylene glycol is higher. Moreover, they also have decreased toxicity and antigenicity and further exhibit an effect of enhancing the solubility of a sparingly water-soluble compound having a high hydrophobicity.
Thus, a polyalkylene glycol and a polyalkylene glycol derivative obtained by introducing a reactive group into the polyalkylene glycol have been important materials indispensable in the field of drug delivery systems. Because of pharmaceutical applications, a polyalkylene glycol derivative containing a particularly small amount of impurities and having high purity have been demanded. Moreover, since improvement in half-lives in blood is more expectable as the molecular weight increases, high-molecular-weight one having a molecular weight of 30000 or more has been recently demanded. Based on such backgrounds, a production technology capable of producing a polyalkylene glycol derivative having high purity and high molecular weight has been strongly desired.
As an impurity contained in a polyalkylene glycol derivative, a diol compound having two hydroxyl groups and having a molecular weight double the molecular weight of the objective compound may be first mentioned. Usually, at the production of a polyalkylene glycol derivative having one hydroxyl group, the derivative can be obtained by addition polymerization of an alkylene oxide using a corresponding alcohol as an initiator and an alkali catalyst. On this occasion, in the case where water is present in the reaction system including the starting materials and a reaction vessel, the alkylene oxide adds and polymerizes to the water molecule and as a result, the diol compound having the hydroxyl groups at both ends and having a molecular weight double the molecular weight of the objective compound is produced as a by-product. Since the diol compound is a polyalkylene glycol the same as the objective compound, they closely resemble each other in physical properties and hence separation and purification are difficult, particularly industrial separation and purification are difficult. In the case where a polyalkylene glycol derivative containing a large amount of the diol compound is subjected to introduction of a reactive group and activation and then reacted with a physiologically active substance such as a protein, the reactive group is introduced into both ends of the impurity diol compound, so that an impurity where the physiologically active substance is introduced into the both ends is produced as a by-product and thus the quality of the resulting pharmaceutical is deteriorated.
For such a reason, control of water content in the reaction system is very important in order to obtain a highly pure polyalkylene glycol derivative containing a lesser amount of the diol compound. Particularly, in the case of producing a high-molecular-weight compound having a molecular weight of more than 30000, a difference in molecular weight between the objective compound and the initiator becomes large, so that the amount of the initiator alcohol to be charged into the reaction vessel becomes small. For example, in the case where the initiator is methanol, the amount of the initiator to be charged is 0.1% by mass or less based on the objective compound and hence there are problems that stirring in the reaction vessel is difficult and as the amount to be charged decreases, the influence of mixed water increases to result in production of a large amount of the diol compound as a by-product. Moreover, the water in the system can be removed under reduced pressure after the starting material alcohol and a catalyst are charged into the reaction vessel but, particularly in the case where the boiling point of the initiator alcohol is close to that of water or in the case where the boiling point is lower than that of water, the starting material initiator also vaporizes together with the water at the operation of dehydration, so that the production of the objective compound has been found to be difficult.
As a process for synthesizing a highly pure polyalkylene glycol derivative, Patent Document 1 proposes a process for producing an oxirane derivative. In the production process, attention is paid on the aforementioned water content in the reaction system but there is no suggestion on the production of a high-molecular-weight compound and no specific examples exist.
Moreover, with regard to the problem that the amount of the initiator alcohol becomes small, Patent Document 2 proposes a production process with diluting the alcohol with an ether solvent beforehand. In this process, the problem relating to stirring is solved but, on the other hand, the problem relating to the water derived from the ether solvent used for dilution is not solved. With regard to the diluting solvent, it is charged to the reaction vessel after dehydration using a column of active alumina, a column of molecular sieves, or the like. However, since the operation of dehydration of the diluting solvent using such a column generally requires a long period of time and also requires a dedicated equipment, the process is suitable for small-scale production but is not suitable for industrial production. Furthermore, as the molecular weight of the objective compound becomes high, the amount of the initiator becomes small, so that the influence of the water mixed in a minute amount increases on the initiator in a molar ratio even when the dehydration is performed by the column operation as described above and as a result, the content of the diol compound derived from the water increases. Particularly in recent years, in the field of the drug delivery systems, a high-molecular-weight compound having a molecular weight of more than 30000 is demanded from the viewpoint of improving the circulation in blood. In the process of Patent Document 2, the diol compound is liable to be produced as a by-product at the production of the high-molecular-weight compound.